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von Mikecz research group: environmental noxae and cell nucleus

Research profile

The research group von Mikecz investigates the effects of environmental noxae / pollutants on the structure and function of the cell nucleus. Here, the ubiquitin-proteasome system fulfills a prominent role by maintaining cellular quality control and protein homeostasis. The research group contributed to define a nuclear ubiquitin-proteasome system and characterize its role in nuclear processes such as transcription. Consistent with this it could be shown that pollutants such as certain trace metals and nanoparticles modify proteasome-dependent proteolysis and promote the formation of amyloid-like protein aggregates in the nucleus. These amyloid-aggregates represent proteolytic centers that recruit components of the ubiquitin-proteasome system, heat shock proteins and RNA processing factors during pollutant-induced stress responses. The pollutant-stress-induced nuclear aggregates resemble neuronal nuclear inclusions that occur in neurodegenerative aggregation diseases. Thus, the characterization of nuclear protein fibrillation mechanisms serves both, a better understanding of molecular effects of noxae and the cellular pathways of neurodegenerative diseases. Consistently, the von Mikecz group demonstrates in cell culture and in the nematode C. elegans that silica nanoparticles and the trace metal mercury induce amyloid protein aggregation in neural cells that inhibits neural transmission and promotes neurodegeneration. Such neurotoxicity manifests in C. elegans by impairment of neuromuscular behavior phenotypes that are otherwise associated with organismal aging processes.

The following projects investigate the underlying pathways of xenobiotic-induced impairment of nuclear quality control:

1. A project investigates nanoparticle-induced protein aggregation in the cell nucleus. What is the function of nuclear protein aggregates? Do they represent centers of proteasomal protein degradation? Are relevant nuclear proteins degraded and does this lead to altered gene expression? How does nanoparticle-effected gene expression impact neural function, e.g. neural transmission? This project aims at development of sustained nanotechnologies by (i) identification of the molecular basics of nanoparticle-induced amyloid formation in the cell nucleus and (ii) addressing concerns that this aberrant protein aggregation could contribute to neurodegenerative processes / aggregation diseases. Model systems used are the culture of neural cells and the nematode roundworm Caenorhabditis elegans.

This project is realized in cooperation with the Neuroscience Network Düsseldorf and the working group Hemmerich at the Leibniz Institute for Age Research in Jena. It was funded by the DFG until 2014. A new grant proposal is under consideration.

2. Another project investigates the pathways of amyloid formation in the cell nucleus. Structural description of stepwise protein fibrillation to amyloid-aggregates has seen considerable progress in vitro, however, methods for the analysis of intracellular protein aggregation processes are still in their infancy. The working group von Mikecz translates the in vitro methods to formation of intracellular amyloid structures that are generally referred to as intracellular inclusions. Silica nanoparticle- or inorganic-mercury(I-Hg)-based methods are used to induce insoluble, nuclear inclusions that exactly mimic neural inclusions that are observed in neurodegenerative aggregation diseases concerning their protein composition and biochemical properties (Chen and von Mikecz, Exp Cell Res 305: 51, 2005; Chen et al., J Cell Biol 180: 697, 2008; Arnhold and von Mikecz, Integr Biol, 2011). I-Hg reduces the solubility of endogenous nuclear proteins including those with homopolymeric polyQ repeats. By application of discrete mathematics on distribution patterns of amyloid-binding compounds a method is introduced that allows for the identification of distinct steps of intranuclear protein aggregation. This technique likewise promotes the development of pattern recognition for (automated) detection of intracellular protein fibrillation.

Funding is provided by graduate schools, GRK 1033 until 6/2014 and iBRAIN since 7/2014. It is realized in cooperation with the working groups that participate in the graduate schools and the Neuroscience Network Düsseldorf.

3. There is currently urgent need to understand in vivobioavailability and effects related to nanoparticle exposure across wildlife species to protect the natural environment. Within the eco-nanotoxicology workpackage of the EU project NanoMILE we test the hypotheses that specific features of nanomaterials confer significant biological effects through the use and application of modified nanoparticles and identify common effects across a wide range of wildlife taxa, spanning from single-celled organisms to lower vertebrates (fish). Conducting effects analysis across a wide range of taxa, aims at determination which organisms are likely to be vulnerable for potential harm allowing for more targeted impact analyses and also start to identify common effect mechanisms. This program includes studies on nanoparticles that are currently used in industrial applications and assessments on whether aging in natural matrices enhances or reduces toxicity in exposed organisms. Comparative analyses are performed cross-species from algae to fish, including C. elegans as a free-living nematode that populates the solid to liquid phase of soil. Investigations in C. elegans include long-term exposure, e.g. life span and reproduction, as well as characterization of protein homeostasis in the nematode. A specific aim is to translate the results from in vitro / cell culture studies and in vivo experiments in rodents for identification of common effect mechanisms.

This project is funded by the EU Consortium NanoMILE and realized in cooperation with the working groups of the consortiums, in particular the working group Schins (IUF).

Cooperations

IUF internal:Krutmann research group / team UnfriedSchins research groupVentura liaison research group